The overall goal of this project is to determine whether the brain stem norepinephrine system plays a role in the mechanisms by which common life stresses (i.e., dieting, moderate exercise and psychological stress) impair activity of the reproductive axis. We have utilized a monkey model of Functional Hypothalamic Amenorrhea (FHA;a clinical condition which accounts for as much as 30% of female infertility), in which monkeys are exposed to psychological stress (moving to a new room) and moderate metabolic stress (a 20% decrease in calorie intake and moderate running for an hour a day, 5 days a week). As occurs in women, some female monkeys are stress-sensitive (SS), and have an immediate impairment of menstrual cycles when exposed to this combination of common life stresses, whereas other female monkeys are medium stress resilient (MSR) ovulate once before amenorrhea and others are highly stress-resilient (HSR) and ovulate during stress. We have substantial evidence that SS females have lower CNS serotonergic function and an up- regulation of neural systems that are inhibitory to GnRH neuronal activity, thereby making them more sensitive to stress-induced suppression of the reproductive axis. However, norepinephrine (NE) plays a pivotal role in the stress response, in the regulation of LH secretion and in the homeostasis of the reproductive system. Moreover, serotonin inhibits the NE neurons of the locus coeruleus (LC) nucleus in the brain stem. This means that the reduction in serotonin in the SS animals may lead to chronic over-activation of NE neurons in the LC, and over-activation of these neurons has been implicated in anxiety disorders. Thus, it is noteworthy that SS monkeys also exhibit higher levels of behavioral agitation, a nonhuman primate manifestation of anxiety. Therefore, in the current proposal we will test the hypothesis that elevated activity of the NE system in the LC is also in part responsible for the suppression of the reproductive axis in stress-sensitive monkeys. Aim 1 will conduct pilot studies to determine the physiological function of the NE system in SS and HSR monkeys and to determine if the antianxiety medication, reboxetine, will prevent stress-induced reproductive dysfunction. Aim 2 will determine the expression of pivotal genes and proteins in the NE neurons of the LC and examine the fiber density of stress-related afferent innervation of the LC in SS, MSR and HSR monkeys in the presence and absence of stress. PUBLIC HEALTH RELEVANCE: We have developed a paradigm that discriminates stress-sensitive from stress-resilient macaques. The goal of this grant is to determine the function of the brain stem noradrenergic system in individuals with different sensitivities in the presence and absence of stress, and to determine if a selective norepinephrine uptake inhibitor can prevent stress-induced reproductive dysfunction. The outcome may suggest a novel treatment for Functional Hypothalamic Amenorrhea.